Prostate cancer is the second leading cause of male cancer deaths in the U.S., but it is the most frequently diagnosed cancer in men. Although current therapeutic radiation strategies are successful in treating the initial cancer, there are fw effective therapeutic options for patients with aggressive prostate cancer. Addition of cytotoxic or hormone therapy offers some benefit, but each is associated with unwanted side effects to normal tissues. The goal of this research project is to develop an anticancer regimen that improves the efficacy of radiation therapy by sensitizing tumor tissue to radiation while simultaneously protecting normal tissue against the side effects of radiation therapy. It addresses the critical gap in scientific knowledge of how the intrinsic differences in the redox conditions of normal and tumor cells trigger differential adaptive responses to prooxidants, and demonstrates the outcome of the proposed approach in a preclinical setting with the expectation that changes in clinical practice could result. We propose that the differences in redox homeostasis in normal and cancer cells create a therapeutic window for pushing cancer cells towards oxidative stress overload and death while stimulating adaptive responses in normal cells to enhance survival. Our preliminary data show that dimethylaminoparthenolide (DMAPT), a lactone water soluble prodrug of parthenolide, selectively sensitizes prostate cancer cells to ionizing radiation (IR), but protects normal prostate epithelial cells against IR-induced injury. W screened a library of 760 FDA-approved compounds for drugs that can radiosensitize tumor cells but radioprotect normal cells and identified betamethasone (BET), a steroid, as a lead compound with these properties. Interestingly, both DMAPT and BET exhibit opposing effects in normal vs cancer cells on RelB, a member of the NF-?B alternative pathway. These results are very important as they allow us to focus on testing a concept and pathway rather than on a specific agent. This proposed study involves proof-of-concept studies in experimental animal models coupled with in-depth mechanistic molecular and cellular studies, using DMAPT and BET. Aim 1 will test the concept that aberrant redox conditions of cancer cells enables a redox-based approach that enhances radiation therapy efficacy by sensitizing cancer cells to radiation treatment while protecting normal cells from the side effects of radiation therapy of prostate cancer. Aim 2 will test the hypothesis that RelB mediates the effect of DMAPT and BET in protecting normal cells but sensitizing prostate cancer cells to IR. The results of this study wil facilitate the translation of novel radiation sensitizers for clinical use and will fill in critica gaps in scientific knowledge of how the differences in redox conditions of normal and tumor cells trigger differential responses to pro-oxidants. Translation of this paradigm-shifting concept will have a major impact on the efficacy and morbidity of radiation therapy.